This proposal is for the establishment of a UCSF/Children's Hospital Oakland Clinical Center in an NIHsupported network charged with conducting clinical trials of therapies for asthma in adults and children, including patients with severe asthma. As examples ofthe Clinical Trials this network could conduct, this application describes two studies. One trial derives from evidence on the importance of vitamin D for innate defense mechanisms in the bronchial epithelium. This trial would compare the effects of two doses of vitamin D on the frequency of asthma exacerbations in children: the current recommended dose of 400 IU/ day vs. the higher but well-tolerated dose of 2000 lU/day. The second trial examines the effects of treatment of asthma exacerbations with the antibiotic, azithromycin. Use of this antibiotic is common practice in treating asthma exacerbations, but rests on an extraordinarily slender body of evidence. Only one of (only) three previous studies showed any benefit, and that study examined a different antibiotic and showed small and inconsistent effects. Given the effects of widespread use of an antibiotic on the costs of care and on the emergence of resistant organisms, we believe the actual benefit of azithromycin treatment of asthma exacerbations needs to be determined. We also believe that such a study should examine a large enough population to allow examination of differential responses in sub-groups, such as those with symptoms of purulent bronchitis or sinusitis, those with positive culture or PCR for potential bacterial pathogens, and those with evidence of respiratory viral infection by PCR testing of sputum or nasal lavage samples. This proposal also describes two Concept studies of mechanisms of asthma that an NIH AsthmaNet network could undertake: one applying a highly novel, culture-independent method, the PhyloChip to examine differences in the bronchial microbiota in asthmatic patients regularly using - or naive to - inhaled corticosteroid treatment, how these bacterial populations are alTected by prolonged azithromycin treatment, and whether these effects are related to the effects of such treatment on markers of asthma control. The second concept study will examine the effects of an 1L-4/IL-13 receptor-antagonist on markers of airway remodeling by applying Designed-Based Stereology to bronchial biopsies obtained before and after treatment. The straightforward nature of these studies, the resources of UCSF/CHRCO, and the highly diverse nature of the populations they serve, will ensure generalizability to clinical practice of the findings made.